UNC3230 is a PIP5K1C inhibitor. It lowered PIP2 levels in DRG neurons and attenuated hypersensitivity when administered intrathecally or into the hindpaw.
PIPKIγ, a key member of the type I phosphatidylinositol 4-phosphate kinase (PIPKI) family that regulates the spatial-temporal generation of PIP2, has been implicated in diverse biological processes including cell survival, cell polarity, and cell migration[1]. PIPKIγ was frequently upregulated in colorectal cancer and predicted a poor prognosis. Genetic silencing of pan-PIPKIγ suppressed cell proliferation and aerobic glycolysis of colorectal cancer. In contrast, the opposite effects were observed by overexpression of PIPKIγ_i2. Importantly, PIPKIγ-induced prolific effect was largely glycolysis-dependent. Mechanistically, PIPKIγ facilitated activation of PI3K/Akt/mTOR signaling pathways to upregulate c-Myc and HIF1α levels, which regulate expression of glycolytic enzymes to enhance glycolysis. Moreover, pharmacological inhibition by PIPKIγ activity with the specific inhibitor UNC3230 significantly inhibited colorectal cancer glycolysis and tumor growth[2]. UNC3230 is a potent, selective and ATP-competitive PIP5K1C inhibitor with an IC50 of ~41 nM. UNC3230 also inhibits PIP4K2C and does not inhibit any of the other lipid kinases that regulate phosphoinositide levels. UNC3230 has antinociceptive and anticancer effects. Membrane PIP2 levels are significantly reduced by ~45% in dorsal root ganglia (DRG) neurons treated with 100 nM UNC3230 (~2-fold above the IC50) relative to vehicle controls. UNC3230 significantly reduces lysophosphatidic acid (LPA)-evoked calcium signaling in cultured DRG neurons relative to vehicle. UNC3230 (2 nmol) significantly increases noxious heat-evoked paw withdrawal latency for two hours after intrathecal injection in wild-type mice, indicating an antinociceptive effect. UNC3230 (2 nmol; intrathecal injection) is administered then one hour later co-injected 1 nmol LPA with UNC3230 (2 nmol, intrathecal injection). UNC3230 significantly blunts thermal hyperalgesia and mechanical allodynia compared to vehicle.UNC3230 (2 nmol; intrathecal injection) significantly blunts thermal hyperalgesia and mechanical allodynia in the complete Freund’s adjuvant (CFA)-inflamed hindpaw (relative to vehicle control) but does not affect thermal or mechanical sensitivity in the control (non-inflamed) hindpaw over a multiday time course[3].
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